The Treatment Evolution…

Better, kinder, easier to take, more tolerable treatments have been the pursuit of HIV drug development research for decades now. Although we have now arrived at a place where a single daily pill may be all that’s currently required for most people (at least for initial treatment), there is more to do to improve the status-quo – particularly for greater convenience, improved long-term tolerability and continuing treatment options.

HIV treatment research development is presently heading down two distinct directions to achieve these ends:

Optimising existing treatments

Whilst current treatments are generally easier to tolerate and easier to take than the drugs of two decades ago, there is a shift to make present daily treatments even better. The most significant recent change has been with the long time ‘backbone’ drug, tenofovir (TDF). The old recipe (TDF) is being replaced with the less troublesome TAF-based lower dose formula – which has much less impact on kidney health and bone mineral density loss.

A number of new TAF-based treatments are now available such as Genvoya (the successor to Stribild), and re-formulations of Truvada and Eviplera – these are known as Descovy (TAF/FTC) and Odefsey (TAF/FTC/rilpivirine). While Descovy has been registered for use in Australia, it awaits listing on the Pharmaceutical Benefits Scheme (PBS – patient co-payment subsidy), before we may see it more broadly used. Whether Odefsey will be registered in Australia is yet unknown, but it is expected to arise soon.

The long familiar booster drug ritonavir is also now tending to be less used, in preference to the new cobicistat booster. COBI as it’s nicknamed, is appearing combined in one pill in a number of new formulas – such as Evotaz (the new version of Reyetaz [atazanavir]) and Prezcobix (the new version of Prezista [darunavir]). It’s the convenience of having a single daily pill that is the driving force here, but Evotaz or Prezcobix are still not complete three active-drug regimens, meaning additional ‘backbone’ drugs must be taken with them. Thus, a further development is in the pipeline combining Prezcobix (darunavir + cobicistat) with Descovy (TAF/FTC) all together in a complete single tablet regimen.

Bictegravir (GS 9883) is also a new integrase inhibitor which is well into development pipeline, and is expected to feature in a single tablet regimen with Descovy (TAF/FTC) in the not too distant future. It will likely be beneficial for people with existing integrase inhibitor resistance, improving the options in that drug class. It may provide better binding to the HIV integrase enzyme, and therefore be more potent.

Meantime, other conventional triple combination regimens are being revisited within studies. The Integrase Inhibitor Dolutegravir, for example, is being studied (for initial treatment) in combination with 3TC (lamivudine) as dual (2 drug) therapy. It is also being paired with rilpivirine (a non-nuke) in the hope that it will maintain undetectable viral load (among people with long treatment histories and drug resistance) – Dolutegravir is a good candidate for this research as it has high barrier to resistance. The benefit of these studies is to also reduce treatment-related side effects (and costs) – by excluding nuke drugs (such as TAF/FTC and Abacavir/3TC) so often held to be the essential ‘backbone’ of treatment. Dolutegravir single drug (monotherapy) studies are also being conducted (among treatment experienced patients). These studies are ongoing, so generally triple therapy is still the convention, especially for commencing initial treatment.

Dosing levels may also change in the future. A current study of the first generation integrase inhibitor raltegravir (Isentress) – currently approved as a twice-daily treatment only – is also being investigated for once-daily dosing, in the hope to improve its convenience.

Towards Greater Horizons

Researchers are moving away from merely simplifying and optimising existing treatments. Eyes are set on less frequent dosing (weekly or monthly, or possibly less) with a new evolution of long-acting treatments that are getting close to the horizon in late stage trials. Additionally, new drug targets (never seen before) are also on the horizon.

A new long-acting (small molecule) injectable integrase inhibitor – cabotegravir – combined with an injectable form of rilpivirine (Edurant), given every four weeks, will enter Phase III trials latter this year, with first results expected within the next two years. The Phase IIb LATTE-2 trial tested intramuscular injections given every four and eight weeks and found that the more frequent dosing schedule suppressed HIV more effectively. This new strategy is being met with much excitement and anticipation to completely change the HIV treatment landscape.

Monoclonal antibodies may also soon become an alternative to daily antiretroviral treatments; they are also being looked at by vaccine (prevention) researchers. Neutralising antibodies are produced by immune B cells and may control (or prevent) certain HIV strains when provided in a synthesised drug format. One called VRC01 given as an infusion has shown particular promise combatting HIV in an early Phase I study.

Other broader and more potent neutralising antibodies have also been identified, with the aim of producing formulations that could be more conveniently injected (rather than infused). Two other therapeutic antibodies – PRO 140 and ibalizumab – have each recently entered late Phase III trials as potential treatments.

PRO140is a weekly injectable, which blocks HIV from entry at the cell surface preventing ongoing HIV replication. There is some concern that weekly injections will not be convenient to some people (particularly they’re to be administered in a clinic setting), but it is still considered an advance on current daily treatment. Also weekly injections may be better tolerated (than longer acting monthly injections) as they remain in the body for relatively shorter periods, limiting higher drug concentration exposure side effects or the development of drug resistance (since levels are topped up to adequate levels more frequently between doses).

Ibalizumabrequires an infusion (rather than an injection) but is currently being evaluated at doses once every two or four weeks.

Both PRO140 and ibalizumab are potentially being considered for people who may have cross-class- resistance to current ARV treatment. Of course, we have seen one other injectable drug in HIV in the distant past for this purpose – Fuzeon (T20 – entry inhibitor) – but it was not long acting (injected twice daily) and its use was eventually limited, due to injection site reactions and other new ARV treatments which also came along shortly after. However, enthusiasm is high for the new longer acting monthly injectables which potentially offer a much broader and more durable application.

New classes of ARV treatments are being developed working to inhibit other steps in the HIV viral replication lifecycle that have not previously been available with existing drug classes. A new class of oral drugs called Maturation inhibitors (which stop new virus particles from ‘maturing’) are in late Phase II/III development, such as BMS-955176.

Although we already have one attachment inhibitor – maraviroc/Celsentri – it works less effectively when HIV uses a host immune cell receptor called “X4” to gain entry into the cell. However, a new attachment inhibitor fostemsavir (currently in phase III late trials) appears to overcome this problem – stopping HIV from latching onto the R5 or X4 co-receptors blocking entry into immune cells. Celsentri (maraviroc), works only for R5 using virus entry pathway, so fostemsavir will be a welcome new entrant.

Still More in The Pipeline

There are number of other drugs further in the development stage that are showing exciting enhanced attributes on existing classes of drugs, such as MK-8591 (an NRTI – nuke) which may allow for weekly oral dosing – which could also extend the time period of dosing of other long acting injectable treatments, if used in combination.

Many of these longer acting compounds are also being evaluated for Pre-Exposure Prophylaxis (PrEP) as part of an enhanced prevention regimen, so we will no doubt hear more about them in that context soon too…

So, meantime, the quest of treatment research continues on a concerted effort to improve quality of life for people living with HIV. With all that is going on we are certainly on the verge of a truly new treatment evolution…